Diverse changes in myelin protein expression in rat brain after perinatal methadone exposure

Rahul Oberoi,Tianci Chu,Jun Cai,Rekha Jagadapillai,Lori A Devlin,Nicholas Mellen,Hezhong Ouyang

doi:10.21307/ane-2019-034

Abstract

The national incidence of neonatal abstinence syndrome has dramatically increased over the last decade due to an increase in antenatal opioid exposure. Recent human and animal studies suggest that antenatal opioid exposure impacts the developing brain. The purpose of this study is to evaluate the effects of perinatal methadone exposure on myelination in multiple regions in the developing rat brain. Pregnant Sprague-Dawley rats were randomly assigned into three experimental groups and subsequently exposed to drinking water alone or drinking water containing methadone from 7 days post coitum through day 7 or through day 19 after delivery. Two male neonatal rats were randomly selected from each litter and terminated at day 19. The cerebral cortex, hippocampus, cerebellum, and brainstem were dissected and analyzed for three myelin specific proteins - CNP, PLP, and MBP - by Western blot analysis. All pups with exposure to methadone demonstrated decreased expression of CNP, PLP, and MBP in the cerebral cortex and hippocampus. In the cerebellum, PLP expression was down‑regulated without apparent alteration of CNP and MBP expression. PLP and MBP expression, but not CNP expression, were significantly inhibited in the brainstem. Compared to the pups with postnatal methadone exposure via maternal milk through day 7, partial recovery of CNP and PLP expression only occurred in the cerebral cortices of the pups exposed through day 19. The findings show that antenatal opioid exposure in rat pups is associated with regionally‑specific alterations in brain myelination that diversely affects myelin proteins.

Highlights

The medical and non‐medical use of opioids has in‐ creased exponentially over the last decade in women of childbearing age (Centers for Disease Control and Prevention, 2016)
cyclic nucleotide 3’‐phosphodiesterase (CNP) is lo‐ calized in immature oligodendrocytes, while proteolipid protein (PLP) and myelin basic protein (MBP) are synthesized in mature oligodendrocytes
An increasing trend in CNP expression and significant decrease in PLP and MBP expression suggest an impairment of oligodendrocyte differentiation and/or myelin forma‐ tion with an impact on immature oligodendrocytes af‐ ter MTD exposure

Summary

Introduction

The medical and non‐medical use of opioids has in‐ creased exponentially over the last decade in women of childbearing age (Centers for Disease Control and Prevention, 2016). An increase in antenatal exposure to opioids has resulted in a greater than 5‐fold rise in the national incidence of neonatal abstinence syndrome (NAS) (Winkelman et al, 2018). A retrospective analysis of infants covered by Medicaid across the United States demonstrated an escalation in incidence of NAS from. The developmental impact of antenatal opioid expo‐ sure remains poorly delineated, but recent human and animal studies provide insight into the influence of ante‐ natal exposure on the structure of the developing brain. Walhovd et al (2007) utilized MRI imaging to demon‐ strate that infants with exposure to illicit psychotropic polysubstances, including heroin during pregnancy, had smaller brain volumes, including white matter volumes, than those not exposed.

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